Pharmaceutical compositions containing sulfonate derivatives of 1,4-bis(propionyl) piperazine

ABSTRACT

Derivatives of 1,4-bis(3-(methylsulfonyloxy)propionyl)piperazine in which the methylsulfonyl groups are substituted by at least one halogeno, cyano or methylsulfonyl group and the piperazine ring optionally bears up to two lower alkyl groups are agents showing activity against transplanted lymphatic leukemia L 1210 in mice. The compounds, of which 1,4-bis(3(chloromethylsulfonyloxy)propionyl)piperazine is a typical embodiment, are obtained through the reaction of the appropriate 1,3-bis(3-iodopropionyl)piperazine and a salt of a substituted methanesulfonic acid.

United States Patent [1 1 Senning et a1.

1451 Dec. 3, 1974 [73] Assignee: F arbenfabriken Bayer Aktiengesellschaft, Leverkusen, Germany [22] Filed: Mar. 23, 1973 [21] Appl. No.: 344,141

Related US. Application Data [62] Division of Ser. No. 180,501, Sept. '14, 1971, Pat.

[30] Foreign Application Priority Data Sept. 18, 1970 Germany 2046087 [52] US. Cl. 424/250 [51] Int. Cl A6lk 27/00 [58] Field of Search 424/250 [56] References Cited FOREIGN PATENTS OR APPLICATIONS 1,177,162 9/1964 Germany 424/250 Primary Examiner -lerome D. Goldberg [5 7] ABSTRACT Derivatives of 1 ,4-bis[ 3- (methylsulfonyloxy)propionyll-piperazine in which the methylsulfonyl groups are substituted by at least one halogeno, cyano or methylsulfonyl group and the piperazine ring optionally bears up to two lower alkyl groups are agents showing activity against transplanted lymphatic leukemia L 1210 in mice. The compounds, of which l,4-bis[ 3- (chloromethylsulfonyloxy)propionyl]piperazine is a typical embodiment, are obtained through the reaction of the appropriate 1,3-bis(3-iodopropionyl)piperazine and a salt of asubstituted methanesulfonic acid.

6 Claims, N0 Drawings PHARMACEUTICAL COMPOSITIONS CONTAINING SULFONATE DERIVATIVES OF l,4-BIS(PROPIONYL) PIPERAZINE each of A and A, independent of the other, is hydrogen or an aliphatic radical;

each of Z and Z, independent of the other, is

halogeno, cyano, pseudo halogeno, or methylsulfonyl and each of X, X, Y and Y is hydrogen, halogeno, cy-

ano, pseudo halogeno of methylsulfonyl.

A preferred group of compounds are those of Formula I wherein A and A are each hydrogen or lower alkyl, 2 and Z are each halogeno, cyano or methylsulfonyl and X, X, Y and Y are each hydrogen, halogeno, cyano or methylsulfonyl.

Aliphatic radicals A and A are identical or different straight-chain or branched alkyl radicals, preferably lower alkyl with 1 to 6, especially 1 to 4, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. Methyl is preferred.

Halo'geno includes fluoro, chloro, bromo and iodo, preferably chloro, bromo and iodo.

Pseudohalogeno includes SCN, OCN, --NCO and N The new sulfonic acid esters are obtained if a diiodo compound of the formula II:

wherein A and A are as defined above s allowed to react with about the stoichiometric amount of a sulfonate of formula 111:

III

wherein X, Y and Z are as defined above, M is a cation which forms a sparingly soluble iodide,

and

n has a value of l or 2.

Compounds of formula I wherein A and A are each hydrogen or the methyl group, and

X, X, Y and Y are each hydrogen, and

Z and Z are each chloro, bromo, iodo or methylsulphonyl are particularly preferred.

The silver cation is especially preferred as an example of the cation M which forms a sparingly soluble iodide.

The starting compounds of the formulas II and III are preferably employed in approximately the stoichiometrically required amounts. The reaction is carried out in the temperature range of from about 20 to about 150C, preferably of about 60 to about preferably in the presence of an organic diluent. Polar aprotic solvents, such as acetonitrile, are preferred. The reaction can however also be carried out without diluents.

The sulfonates (III) which serve as starting compounds are known or can be obtained according to known processes. As examples of such sulfonates there may be mentioned:

(melting point: 155,5157.5C) (decomposes above C) (melting point: 196-198C) (melting point: 184-185C) (melting point: l78-180.5C) (melting point: 255-257C) (melting point: lilo-190C) The reaction can be typified by the following equation:

it 2 c L-+-SO,1 Ag+ The manufacture of the compounds according to the invention will be explained with the aid of the following examples:

thanesulfonic acid is digested with 69 g of silver car- EXAMPLE 1 bonate, whereupon 40 g of silver carbonate remain un- 11.9 gof silver chloromethanesulfonate, 13.0 g of 1,- dissolved and are filtered off. The filtrate is concen- 3 iOdop,-opiony])-piperazine and 100 1 f dry trated in vacuo, with the bath temperature not exceedacetonitrile are heated for 1 hour under reflux, with 5 mg 6000 After adding methanol, 45 g of Crystalline stirring. The warm reaction mixture is filtered, and the Ver methylsulfonylmelhanesulfonate of melting P residue is extracted with boiling acetonitrile. The comlsetlgooc are Obtained bined acetonitrile solutions are concentrated in vacuo, The activity of the compounds according to the whereupon the residue crystallizes out. The residue is Ventlon can be conveniently Observed in the model of successively washed with cold water, ethanol and ether, transplanted lymphatle leukemia L 1210 on mice as and is dried After recrystallization from acetonitrile, fellows: 7.3 g of 1,4-bis-(3-(chloromethanesulfonyloxy)- e welghlllg gfstrain B 6 D F l) were propionyl) piperazine of melting point are ected mtraperrtoneally with 2 X 10 leukemia cells (L Obtained 1210) in 0.2 ml of ascites fluid.

The following are obtained analogously. The treatment was carried out 4 times, on successive days, by intraperltoneal administration, and started 24 EXAMPLE 2 hours after the transplantation of the leukemia cells.

CHz-CH2 CIl1BrS0zO(CH1),=CON \N-CO(CH2)2O-SO2-CII2BY cut-cm k melting point: l46-l48C from 1,4-bis-(3- The duration of the test was 2-3 weeks. iodopropionyl)piperazine and silver bromomethanesul- To assess the results of the test, the survival time fonate. index (ST index) was determined as follows:

EXAMPLE 3 25 1f the survival time 50 of the control group is treated CH2-CH7 t:iI,r-soTo cH:)2-CoN NC0-(crn)10-s02cu2r CHz-Clh c melting point: 136-139C from 1,4-bis-( 3- as 100%, it is possible, using the formula iodopropionyl)piperazine and silver iodomethanesul- ST index ST 50 of the treated group X 100/ST 50 of fonate. the control group EXAMPLE 4 to compute a quotient which can be treated as an index of the change in the ST under the treatment. CH;CH;

cins 02 crn s or-ocrmr-c ON NC o(oH)Z0s o gCHzS 0 Porn CH3-CH2 melting point: 136l43C from 1,4-bis-(3- ASSESSMENT:

iodopropionyhpiperazine and silver methylsulfonylme- 40 Values l00% denote a reduced survival time of the thanesulfonate.

treated group of animals and hence a toxic action of the EXAMPLE 5 P p CI-1zCII(CH-3) cnnn-sm-o-wmx-oo-rv N-UO(ClI1)z0SOgCIhBr ..Q. C QH w melting point: 154.5-l56.5C. from 1,4-bis-( 3- Values lO0% denote an increased survival time 50, iodopropionyl)-2,5-dimethy1piperazine and silver which, depending on the level of the index, express an bromomethanesulfonate. inhibition of the growth of the leukemia cells.

The silver methylsulfonylmethanesulfonate required The results are shown in Table 1.

for the manufacture of the compound described as Example 4 is obtained as follows:

1 14.0 g of methanesulfonyl chloride are added drop- Table 1 Leukemia L 12t0.

wise over the course of 30 minutes to a mixture of 210 optimum dose in mg/kg ml of triethylamine and 400 ml of anhydrous acetoni- S 4 i r fg 2 trile, at -40C, with stirring. The mixture is stirred for e mmpemmm y m a further hour at -4 OfC and 9.0 mlof water are added, Comparison again at 40C. After a further 15 minutes stirring at :8 :32 -40C, the mixture is filtered and the filtrate is concen- 6O 5 10 6 trated in vacuo. After adding 500 ml of 2 N sodium hydroxide, g of crystals of melting point 235 240C The comparison substance used was the compound of the formula:

are obtained, which are filtered off. After recrystallization from ethanol/water, the sodium meth lsulfon 1- methanesulfonate melts between 239 and 231C. 45 g /N Co (Cmrosog.CH3 of sodium methylsulfonylmethanesulfonate are dissolved in 1 liter of water and passed through an ion exchanger column with a polystyrene synthetic resin, from German Patent Specification No. 1,177,162. containing sulfonic acid groups, as the ion exchanger. The new compounds are preferably administered The aqueous solution of the free methylsulfonylmeorally and can be used either as such or in combination with non-toxic, inert, pharmaceutically tolerated excipients. Suitable forms for administration, in combination with various inert excipients, are tablets, dragees, capsules, granules, aqueous suspensions and emulsions, non-aqueous emulsions and suspensions, syrups and the like. Such excipients include solid diluents or fillers, aqueous media, as well as various non-toxic organic diluents and the like. Of course, tablets and the like can be provided with a sweetener and similar substances. The therapeutically active compound should, in the above mentioned case, be present in a concentration of about 0.5 to 90 per cent by weight of the total mixture, in amounts which suffice to achieve dosage range which is effective.

The formulations are manufactured according to conventional techniques, for example by extending the active substances with diluents and/or excipients, optionally using emulsifiers and/or dispersing agents, such as water, non-toxic organic solvents or diluents, such as paraffms, vegetable oils, such as groundnut oil and sesame oil, alcohols, such as ethyl alcohol or glycerol, glycols, such as propylene glycol or polyethylene glycol, solid excipients, such as, for example, natural rock powders for example kaolins, aluminas, talc or chalk, synthetic rock powders, such as highly disperse silica and silicates, sugars as for example unrefined sugar, lactose and glucose; emulsifiers, such as non-ionic and anionic emulsifiers as for example polyoxyethylenefatty acid esters, polyoxyethylene-fatty alcohol ethers, alkylsulfonates and arylsulfonates, dispersing agents, such as lignin, sulfite waste lyes, methylcellulose, starch and polyvinylpyrrolidone and lubricants, such as magnesium stearate, talc, stearic acid and sodium lauryl sulfate.

Apart from the excipients mentioned, tablets can of course also contain additives, such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various further substances such as starch, preferably potato starch, gelatin and the like. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can additionally be used for making tablets. In the case of suspensions and emulsions, the active substances can be mixed with various flavor improving agents or dyestuffs in addition to the above mentioned auxiliaries.

The active substances can also be contained in the form of dosage units in capsules, tablets, pastilles, dragees, ampoules and the like, each dosage unit being so adapted as to yield a single dose of the active constituent.

.The new compounds can also be present in the forln general it has proved advantageous to administer l amounts of about 5 mg to 50 mg/hg of body weight per day to achieve effective results. Nevertheless it will at times be necessary to deviate from the amounts mentioned, and in particular to do so as a function of the body weight of the test animal, the method of administration, the type of animal and its individual behavior towards the agent, the type of formulation, and the administration regimen. Thus it will in some cases suffice to use less than the above mentioned minimum amount, while in others the upper limit mentioned must be exceeded. Where larger amounts are administered, it can be advisable to divide these into several individual administrations over the course of the day.

What is claimed is:

1. A composition comprising in unit dosage form from 0.5 to by weight of a compound of the formula:

in which A and A are each hydrogen or primary or secondary lower alkyl of l to 6 carbon atoms;

Z is chloro, bromo or iodo, and

X and Y are each hydrogen, chloro, bromo or iodo,

and an inert pharmaceutical carrier.

2. A composition according to claim 1 wherein A and A are each hydrogen or methyl; Z is chloro, bromo, iodo and X and Y are each hydrogen.

3. The composition according to claim 1 wherein the compound is l,4-bis[ 3- (chloromethylsulfonyloxy)propionyl]piperazine.

4. The composition according to claim 1, wherein the compound is 1,4-bis-[3- (bromomethylsulfonyloxy)propionyl]-2,5-dimethylpiperazine.

5. The composition according to claim 1, wherein the compound is l,4-bis[ 3- (bromomethylsulfonyloxy )propionyl lpiperazine.

6. The composition according to claim 1, wherein the compound is l,4-bis[ 3- (iodomethylsulfonyloxy)propionyllpiperazine. 

1. A COMPOSITION COMPRISING IN UNIT DOSAGE FROM 0.5 TO 90% BY WEIGHT OF A COMPOUND OF THE FORMULA:
 2. A composition according to claim 1 wherein A and A'' are each hydrogen or methyl; Z is chloro, bromo, iodo and X and Y are each hydrogen.
 3. The composition according to claim 1 wherein the compound is 1,4-bis(3-(chloromethylsulfonyloxy)propionyl)piperazine.
 4. The composition according to claim 1, wherein the compound is 1,4-bis-(3-(bromomethylsulfonyloxy)propionyl)-2,5-dimethylpiperazine.
 5. The composition according to claim 1, wherein the compound is 1,4-bis(3-(bromomethylsulfonyloxy)propionyl)piperazine.
 6. The composition according to claim 1, wherein the compound is 1,4-bis(3-(iodomethylsulfonyloxy)propionyl)piperazine. 